Hereditary Multiple Exostoses: New Insights into Pathogenesis, Clinical Complications, and Potential Treatments

Abstract

Purpose of review: Hereditary multiple exostoses (HME) is a complex musculoskeletal pediatric disorder characterized by osteochondromas that form next to the growth plates of many skeletal elements, including long bones, ribs, and vertebrae. Due to its intricacies and unresolved issues, HME continues to pose major challenges to both clinicians and biomedical researchers. The purpose of this review is to describe and analyze recent advances in this field and point to possible targets and strategies for future biologically based therapeutic intervention.

Recent findings: Most HME cases are linked to loss-of-function mutations in EXT1 or EXT2 that encode glycosyltransferases responsible for heparan sulfate (HS) synthesis, leading to HS deficiency. Recent genomic inquiries have extended those findings but have yet to provide a definitive genotype-phenotype correlation. Clinical studies emphasize that in addition to the well-known skeletal problems caused by osteochondromas, HME patients can experience, and suffer from, other symptoms and health complications such as chronic pain and nerve impingement. Laboratory work has produced novel insights into alterations in cellular and molecular mechanisms instigated by HS deficiency and subtending onset and growth of osteochondroma and how such changes could be targeted toward therapeutic ends. HME is a rare and orphan disease and, as such, is being studied only by a handful of clinical and basic investigators. Despite this limitation, significant advances have been made in the last few years, and the future bodes well for deciphering more thoroughly its pathogenesis and, in turn, identifying the most effective treatment for osteochondroma prevention.

Keywords: Drug treatment; EXT1; EXT2; Genotype-phenotype correlations; Heparan sulfate; Hereditary multiple exostoses; Multiple osteochondromas; Signaling proteins.

Conflict of interest statement

Conflict of Interest

M. Pacifici declares that he is part of a patent application on heparanase as a putative therapeutic target in HME.

Figures

Fig. 1

Schematic illustrates a series of regulatory steps that could cause inception and promotion of osteochondroma formation and growth in HME patients. (A) In healthy wild-type (WT) circumstances, the perichondrium (in yellow) would delineate the boundary with, and closely flank, the growth plate (in blue) of skeletal elements such as long bones. The perichondrial cells would be characterized by typical mesenchymal and fibroblastic traits including: a flat cell morphology; normal EXT expression and HS levels; strong anti-chondrogenic mechanisms including FGF expression and ERK/MEK signaling; and low activity/expression of pro-chondrogenic mechanisms including BMP signaling and heparanase. (B) Up and down arrows depict the high and low levels of respective traits in normal perichondrium. (C) During the course of HME, LOH or another second hit would cause a steep and nearly complete loss of EXT expression and/or HS levels in local cells (in red) along the perichondrial border with the heterozygous EXT mutant growth plate. This would result in steep decreases in anti-chondrogenic pathways and reciprocal increases in pro-chondrogenic pathways and heparanase expression in the mutant cells (depicted in D), thus altering their homeostatic mechanisms and triggering differentiation into round-shaped chondrocytes (in red). The growing osteochondromas would contain a mixture of mutant (red) and heterozygous (blue) cells, the latter being recruited into the osteochondroma forming process by the mutant cells. The changes occurring in the activity of the BMP and FGF signaling pathways and in the expression of heparanase could each offer a plausible therapeutic target and strategy to block osteochondroma inception and/or growth.